Dynamic Plantar Aesthesiometer Research Articles

Comparison of actions of systemically and locally administrated local anaesthetics in diabetic rats with painful neuropathy

Nothing is known about actions of levobupivacaine, a long-acting local anaesthetic belonging to the amino amide group, in diabetes-induced neuropathic pain conditions. In this study, we therefore investigated the possible antihyperalgesic and antiallodynic effects of levobupivacaine in diabetic animal model. Actions of systemically (intraperitoneal) or locally (intraplantar) administrated levobupivacaine on streptozotocin-induced diabetic rats with painful neuropathy were examined using a thermal plantar test and a dynamic plantar aesthesiometer. Effects of levobupivacaine were compared with those of a well-known amide local anaesthetic lidocaine. Levobupivacaine was more potent than lidocaine in all tests employed on diabetic rats. After intraperitoneal injections to diabetic rats, levobupivacaine, but not lidocaine, produced pronounced antihyperalgesic and antiallodynic effects. However, intraplantar administration of both levobupivacaine and lidocaine produced antihyperalgesic and antiallodynic action in diabetic rats. In contrast to the transient effects of lidocaine (30 min), antihyperalgesic and antiallodynic actions of levobupivacaine gradually disappeared within 120 min after intraplantar injections. Intraperitoneal or intraplantar administrations of levobupivacaine or lidocaine at the effective dose had no effect on any parameters in intact rats. Findings revealed that antiallodynic and antihyperalgesic potency of levobupivacaine was higher in comparison with that of lidocaine after their intraperitoneal or intraplantar administration to diabetic animals. Furthermore, locally administrated levobupivacaine has the greatest antihyperalgesic and antiallodynic actions in diabetic rats.

Synergistic anti-allodynic effects of nociceptin/orphanin FQ and cannabinoid systems in neuropathic mice

Combinations of analgesics from different classes are commonly used in the management of chronic pain. The goal is to enhance pain relief together with the reduction of side effects. The present study was undertaken to examine the anti-allodynic synergy resulting from the combination of WIN 55,212-2, a cannabinoid CB1 receptor agonist, and JTC-801, a nociceptin/orphanin FQ receptor antagonist, on neuropathic pain. Mice were tested for behavioral effects before and 2–4weeks after the surgery, in which a partial tight ligation of the sciatic nerve was made. Nerve injury-induced mechanical allodynia was assessed with Dynamic Plantar Aesthesiometer, and a hot/cold plate was used to assess cold allodynia. Both WIN 55,212-2 and JTC-801 produced dose-dependent mechanical and cold anti-allodynic effects. As shown by isobolographic analysis, WIN 55,212-2/JTC-801 combinations interacted synergistically at all three ratios studied in the mechanical allodynia assay. In conclusion, co-administration of a cannabinoid with a nociceptin/orphanin FQ receptor antagonist resulted in a synergistic interaction, which may have utility in the pharmacological treatment of neuropathic pain.

섬유근통 동물 모델에서 포도씨 추출 proanthocyanidin의 진통 효과

산성 식염수 쥐모델은 사람의 섬유근통에 근접한 모델로 제시되고 있다. 포도씨에서 얻은 oligomeric proanthocyanidin complexes (OPC)는 항산화제로 알려져 있다. 저자들은 산성 식염수 모델에서 통증 역치에 대한 OPC의 효과를 연구했다. 좌측 장딴지 근육에 pH 4.0의 산성 식염수 <TEX>$100\;{\mu}l$</TEX>를 0일과 5일에 주사했다. 대조군은 pH 7.2의 생리 식염수를 같은 스케줄로 주사했다. 산성 식염수 그룹 10마리를 다시 두 그룹으로 나누어 한 그룹은 멸균 식염수, 다른 한 그룹은 OPC 300 mg/kg를 복강 내 주사했다. 복강 내 주사 한시간 후 다시 통각에 대한 역치를 조사했다. 0일에 비해 7일에서 산성 식염수 모델은 기계적 과통각을 나타냈다(p<0.05). OPC 300 mg/kg를 복강내 주사한 그룹에서 강력한 항통각 효과를 나타냈다(주사측 발바닥, p=0.001; 반대측 발바닥, p=0.002). 면역조직화학 염색상 복강내 식염수를 처치한 대조군에 비해 OPC 처치군에서 대뇌의 M1 및 M2 영역에서 산-감지 이온 통로3의 발현이 감소되었다(p<0.05). 사람의 섬유근통에서 OPC 치료의 효과를 보기 위한 연구가 향후 필요할 것으로 생각된다. The acidic saline animal model of pain has been suggested to mimic fibromyalgia (FM). Oligomeric proanthocyanidin complexes (OPC) from grape seeds are known to act as an antioxidant. We studied the effects of OPC on the pain threshold in the acidic saline animal model of pain. The left gastrocnemius muscle was injected with <TEX>$100\;{\mu}l$</TEX> of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Control rats (n=5) received identical injections of physiological saline (pH 7.2) on the same schedule. Rats (n=10) with acidic saline injection were separated into two study subgroups. After measurement of pre-drug pain thresholds, rats were injected intraperitoneally with either saline or OPC 300 mg/kg. Paw withdrawal thresholds to pressure were again measured 60 min after intraperitoneal injection. Nociceptive thresholds were measured with a Dynamic Plantar Aesthesiometer by applying an increasing pressure to right or left hind paw until the rat withdrew the paw. Compared to baseline (day 0), acid injections produced mechanical hyper-responsiveness on day 7 (pre-drug) in these rats [p<0.05]. A potent antihyperalgesic effect was observed when rats were injected intraperitoneally with OPC 300 mg/kg [injected paw, p=0.001; contralateral paw, p=0.002]. OPC treatment decreased the expression of acid sensing ion channel 3 in the brain motor cortex area on immunohistochemical staining when OPC 300 mg/kg was administered intraperitoneally in the animal model of FM pain [p<0.05]. Further research is required to determine the efficacy of OPC treatments in FM pain in humans.

Effect of the Combined Use of Tramadol and Milnacipran on Pain Threshold in an Animal Model of Fibromyalgia

Background/AimsAcidic saline injections produce mechanical hyperresponsiveness in male Sprague-Dawley rats. We investigated the effect of milnacipran in conjunction with tramadol on the pain threshold in an acidic saline animal model of pain.MethodsThe left gastrocnemius muscle of 20 male rats was injected with 100 µL of saline at pH 4.0 under brief isoflurane anesthesia on days 0 and 5. Rats administered acidic saline injections were separated into four study subgroups. After determining the pre-drug pain threshold, rats were injected intraperitoneally with one of the following regimens; saline, milnacipran alone (60 mg/kg), milnacipran (40 mg/kg) plus tramadol (20 mg/kg), or milnacipran (40 mg/kg) plus tramadol (40 mg/kg). Paw withdrawal in response to pressure was measured at 30 min, 120 min, and 5 days after injection. Nociceptive thresholds, expressed in grams, were measured with a Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) by applying increasing pressure to the right or left hind paw until the rat withdrew the paw.ResultsA potent antihyperalgesic effect was observed when tramadol and milnacipran were used in combination (injected paw, p=0.001; contralateral paw, p=0.012). This finding was observed only at 30 min after the combination treatment.ConclusionsWe observed potentiation of the antihyperalgesic effect when milnacipran and tramadol were administered in combination in an animal model of fibromyalgia. Further research is required to determine the efficacy of various combination treatments in fibromyalgia in humans.

Contralateral allodynia and central change in the chronic post-ischemic pain model rats

Mirror-image allodynia is a mysterious phenomenon that occurs in association with many clinical pain syndromes including complex regional pain syndromes (CRPS). Underlying mechanisms for the development of such pain are still a matter of investigation. Several studies suggest that activation of the N-methyl-D-aspartate (NMDA) receptor is essential for central sensitization as a base for persistent pain. The aim is to assess whether alteration of NMDA receptor expression correlates with the contralateral allodynia in the chronic post-ischemia pain (CPIP) model rats representing CRPS-Type I. Application of a tight-fitting tourniquet for a period of 3 hours before reperfusion produced CPIP in male Sprague-Dawley rats. The mechanical paw withdrawal thresholds to von Frey stimuli (using a dynamic plantar aesthesiometer) were measured as pain indicators in ipsilateral and contralateral hindpaws. Phosphorylation of the NMDA receptor 1 subunit (pNR1), assessed with Western blot, was measured in the contralateral L4-6 spinal cord. Ipsilateral and contralateral mechanical allodynia is present at 4 hours after reperfusion, peaked at 3 days, and continued for 7 days after reperfusion. The relative density of pNR1 of CPIP rats significantly decreased in the contralateral L4-6 spinal cord compared to baseline value (P < 0.05). There was significant correlation between paw withdrawal threshold and the relative density of pNR1 (ipsilateral; R2 = 0.75, P < 0.01, contralateral; R2 = 0.60, P < 0.01). These data suggest that pNR1 is correlated to the contralateral mechanical allodynia in CPIP rats.

Percutaneous Pulsed Radiofrequency Reduces Mechanical Allodynia in a Neuropathic Pain Model

Neuropathic pain is a result of a primary lesion or dysfunction of the peripheral or central nervous system, and its treatment is challenging. Animal models have been helpful in understanding mechanisms of neuropathic pain and in developing new treatment strategies. In this study, we examined the effect of percutaneous pulsed radiofrequency (PRF), which is a minimally invasive pain treatment method, on mechanical allodynia in a neuropathic pain rat model. Neuropathic pain was achieved in a peripheral nerve pain model by performing L5-6 spinal nerve ligation. On the 14th postoperative day, percutaneous PRF was applied to the plantar side of the left rear paw. Animals were evaluated for mechanical allodynia with both dynamic plantar aesthesiometer (DPA) (weight and paw withdrawal time) and von Frey filaments (VF) on the 14th postoperative day and 1, 3, 5, 7, 10, and 14 days after PRF treatment. Experiments were conducted in six groups: Sham-operated+placebo PRF 6 min, sham-operated+PRF 6 min, neuropathic (NP)+2 min placebo PRF, NP+2 min PRF, NP+6 min placebo PRF, and NP+6 min PRF. Allodynia developed in all animals in the NP groups compared to sham-operated animals (P=0.0001). DPA and VF showed that PRF application for 2 min significantly improved allodynia on 1-14th post-PRF day, compared to placebo PRF (P=0.0001). Although DPA (both weight and paw withdrawal time) did not show any therapeutic effect from 6 min PRF application on 1-14th post-PRF days (P=1.00), VF demonstrated transient improvement for the first week, which disappeared on later evaluations of the 6 min PRF group. Percutaneous PRF is an effective treatment option in the NP pain model, and further studies are needed to clarify its underlying mechanisms of action.

A role for hydrogen peroxide in inflammatory hyperalgesia of the mouse hindpaw

Reactive oxygen species, including hydrogen peroxide (H2O2), are released from activated leucocytes and resident cells in the joint during inflammation. We hypothesize that H2O2 is an important mediator of inflammatory pain and, thus, the aim of our experiments was to investigate the effect of H2O2 on inflammation of the mouse hindpaw. We performed behavioural studies in CD1 mice to determine the effect of H2O2 on both thermal and mechanical hyperalgesia and oedema formation 20 minutes after intraplantar injection into the mouse hindpaw. The Hargreaves technique was used to test thermal hyperalgesia and a dynamic plantar aesthesiometer was used for mechanical hyperalgesia studies. Oedema was determined by measuring paw mass. Our experiments showed intraplantar injection of H2O2 (2200–8800 nmoles) causes significant thermal and mechanical hyperalgesia of the mouse hindpaw. H2O2 also causes significant oedema formation. Thus, we propose that H2O2 is a potential target for the treatment of inflammatory pain.

Blockade of metabotropic glutamate receptor 5 activation inhibits mechanical hypersensitivity following abdominal surgery

This study used the metabotropic glutamate 5 (mGlu5) receptor subtype-selective antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) to characterise the contribution of mGlu5 receptor activity to pain and hypersensitivity in an animal model of post-surgical pain. Adult female Wistar rats (200–250 g) were anaesthetised with isoflurane (2%) and underwent a midline laparotomy with gentle manipulation of the viscera, and the effects of pre- (30 min) or post- (5 h) operative treatment with MPEP (1, 3 or 10 mg kg −1; i.p.) or drug-vehicle on hindpaw withdrawal latency (in seconds) to thermal stimulation (Hargreave’s Test) and response threshold (in grams) to mechanical stimulation (using a dynamic plantar aesthesiometer) were measured. Animals that underwent surgery displayed significant hypersensitivity to mechanical stimulation of the hindpaws. Hypersensitivity was maximum at 6 h post-surgery (44.5 ± 2.4% decrease; p < 0.01 vs. anaesthesia only controls) and persisted for 48 h. Surgery had no effect on thermal withdrawal latency. Both pre-operative and post-operative administration of 10 mg kg −1MPEP blocked mechanical hypersensitivity induced by surgery ( p < 0.01 vs. vehicle treatment). MPEP had no effect on acute nociceptive thresholds in naïve animals. These data suggest that activity at mGlu5 receptors contributes to development of pain and hypersensitivity following surgery.

Quantitative assessment of forelimb motor function after cervical spinal cord injury in rats: Relationship to the corticospinal tract

Approximately 50% of human spinal cord injuries (SCI) are at the cervical level, resulting in impairments in motor function of the upper extremity. Even modest recovery of upper extremity function could have an enormous impact on quality of life for quadriplegics. Thus, there is a critical need to develop experimental models for cervical SCI and techniques to assess deficits and recovery of forelimb motor function. Here, we analyze forelimb and forepaw motor function in rats after a lateral hemisection at C5 and assessed the relationship between the functional impairments and the extent of damage to one descending motor system, the corticospinal tract (CST). Female Sprague–Dawley rats were trained on various behavioral tasks that require the forelimb, including a task that measures gripping ability by the hand (as measured by a grip strength meter, GSM), a food reaching task, and horizontal rope walking. After 8 weeks of post-injury testing, the distribution of the CST was evaluated by injecting BDA into the sensorimotor cortex either ipsi- or contralateral to the cervical lesion. Complete unilateral hemisection injuries eliminated the ability to grip and caused severe impairments in food retrieval by the forepaw ipsilateral to the lesion. There was no indication of recovery in either task. In cases in which hemisections spared white matter near the midline, there was some recovery of forelimb motor function over time. Assessment of rope climbing ability revealed permanent impairments in forelimb use and deficits in hindlimb use and trunk stability. Sensory testing using a dynamic plantar aesthesiometer revealed that there was no increase in touch sensitivity in the affected forelimb. For the cases in which both histological and behavioral data were available, spared forelimb motor function was greatest in rats in which there was sparing of the dorsal CST.

Peripheral Effect of Neostigmine and L-NAME on Acute Arthritis in the Rat

Background: The spinal administration of neostigmine has been shown to produce analgesia, but this analgesia is limited by adverse effects. This study was designed to determine whether intra-articular neostigmine results in an analgesic effect in a rat inflamed knee joint model, and to investigate the possible involvement of nitric oxide in neostigmine-induced analgesia. Methods: Male Sprague Dawley rats were divided into three groups; control group, neostigmine group (1, 3, 10), and L-NAME group (neostigmine 1, 3, 10 + L-NAME 500). Inflammation was induced by injecting 2% carageenan into the right knee joint. Intraarticular drugs were injected at an hour after the injection of carageenan. Effects of these drugs were assessed before and at 4, 8, 12, 24, 60, and 120 hours after inflammation using a Dynamic plantar aesthesiometer. Results: There were significant differences between the neostigmine 3, and 10 group and the control group. There were no significant differences between the neostigmine group and the L-NAME group except for in the neostigmine 10 L-NAME group at 24 hours. There were no significant differences between the neostigmine 3 L-NAME group and the control group. This result shows that injection of L-NAME partially reverses the anlgesic effects of the neostigmine. Conclusions: Intra-articular neostigmine results in an analgesic effect at the site of inflammation. Although this study could not prove the involvement of nitric oxide in the peripheral analgesic effect of neostigmine, it demonstrates the possible involvement of nitric oxide in neostigmine-induced analgesia.